Venous malformations (VMs) are bluish-purple lesions that can be single or multiple (Vikkula et al. 1998). They are most often localized on the skin and mucous membranes. In two families in which these lesions are inherited as an autosomal dominant trait, a locus (VMCM1) was identified on chromosome 9p21 that is linked to the phenotype (Boon et al. 1994; Gallione et al. 1995). It was found that the mutation in this locus is in the gene encoding the endothelial-specific receptor tyrosine kinase TIE-2. The R849W mutation in the intracellular kinase domain of TIE-2 leads to hyper-activation of the receptor in a ligand-independent manner (Vikkula et al. 1996). Another amino acid substitution, Y897S, identified in a separate family, seems to have a similar effect (Calvert et al. 1999).
Recently a second locus (VMGLOM) was identified on chromosome 1p21-22 for a subtype of VMs called “glomangiomas” because of the presence of undifferentiated smooth-muscle cells (“glomus cells”) in histological slides (Boon et al. 1999). Three positional candidate genes: DR1 (depressor of transcription 1), TGFBR3 (transforming growth factor-β receptor, type 3) and TFA (tissue factor) were screened and excluded. The identification of a candidate gene in the 5 Mbp VMGLOM locus would allow detection of mutations involved with venous malformations. It is thus an aim of the present invention to provide nucleic acid sequences representing genes involved with disorders with a vascular component as well as methods for diagnosis and treatment of disorders with a vascular component.